A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation

Park, Ji Seon,Bae, Su Jung,Choi, Sik-Won,Son, You Hwa,Park, Sung Bum,Rhee, Sang Dal,Kim, Hee Youn,Jung, Won Hoon,Kang, Seung Kyu,Ahn, Jin Hee,Kim, Seong Hwan,Kim, Ki Young Society for Endocrinology 2014 Journal of molecular endocrinology Vol.52 No.2

<P>Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11β-HSD1 inhibitor. Cellular 11β-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50 mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The <I>in vitro</I> anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The <I>in vitro</I> anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the <I>in vivo</I> glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11β-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.</P>

Possible involvement of food texture in insulin resistance and energy metabolism in male rats

Bae, Cho-Rong,Hasegawa, Kazuya,Akieda-Asai, Sayaka,Kawasaki, Yurie,Senba, Kazuyo,Cha, Youn-Soo,Date, Yukari Society for Endocrinology 2014 The Journal of endocrinology Vol.222 No.1

<P>Food texture is known to affect energy metabolism. Although feeding with soft pellets (SP) or via a tube is known to cause increases in body weight, it is unclear how different food textures influence energy metabolism. In this study, we investigated the effects of two different food textures on energy balance and glucose and lipid metabolism in male Wistar rats. The rats were fed SP or control pellets (CP) on a 3-h restricted feeding schedule for 14 weeks and their energy intake, body weight, and energy expenditure were examined. The levels of gastrointestinal hormones, glucose and insulin, were investigated at pre-, mid, and post-feeding. Glucose tolerance and insulin tolerance tests were conducted, and the expressions of molecules involved in the insulin signaling system or lipogenesis in the liver were examined. Histological investigation of pancreatic islets was carried out using anti-insulin and anti-Ki-67 antibodies. Furthermore, the expression in the liver and circulating blood of microRNA-33 (miR-33), which regulates insulin receptor substance 2, was examined. There were no significant differences in energy intake, body weight, or gastrointestinal hormone levels between the SP and CP rats; however, the SP rats showed glucose intolerance and insulin resistance with disruption of insulin signaling. Increases in lipogenic factors and miR-33 expression were also found in the SP rats. The numbers of insulin-positive areas and Ki-67-positive cells of SP rats were significantly increased. This study shows that a soft food texture causes diabetes without obesity, so differences in food texture may be an important factor in type 2 diabetes.</P>

Melanocortins induce interleukin 6 gene expression and secretion through melanocortin receptors 2 and 5 in 3T3-L1 adipocytes

Jun, Dong-Jae,Na, Kyung-Yoon,Kim, Wanil,Kwak, Dongoh,Kwon, Eun-Jeong,Yoon, Jong Hyuk,Yea, Kyungmoo,Lee, Hyeongji,Kim, Jaeyoon,Suh, Pann-Gill,Ryu, Sung Ho,Kim, Kyong-Tai Society for Endocrinology 2010 Journal of molecular endocrinology Vol.44 No.3

<P>Interleukin 6 (IL6) is a pleiotropic cytokine that not only affects the immune system, but also plays an active role in many physiological events in various organs. Notably, 35% of systemic IL6 originates from adipose tissues under noninflammatory conditions. Here, we describe a previously unknown function of melanocortins in regulating <I>Il6</I> gene expression and production in 3T3-L1 adipocytes through membrane receptors which are called melanocortin receptors (MCRs). Of the five MCRs that have been cloned, MC2R and MC5R are expressed during adipocyte differentiation. α-Melanocyte-stimulating hormone (α-MSH) or ACTH treatment of 3T3-L1 adipocytes induces <I>Il6</I> gene expression and production in a time- and concentration-dependent manner via various signaling pathways including the protein kinase A, p38 mitogen-activated protein kinase, cJun N-terminal kinase, and IκB kinase pathways. Specific inhibition of MC2R and MC5R expression with short interfering <I>Mc2r</I> and <I>Mc5r</I> RNAs significantly attenuated the α-MSH-induced increase of intracellular cAMP and both the level of <I>Il6</I> mRNA and secretion of IL6 in 3T3-L1 adipocytes. Finally, when injected into mouse tail vein, α-MSH dramatically increased the <I>Il6</I> transcript levels in epididymal fat pads. These results suggest that α-MSH in addition to ACTH may function as a regulator of inflammation by regulating cytokine production.</P>

Suppression of autophagic activation in the mouse uterus by estrogen and progesterone

Choi, Soyoung,Shin, Hyejin,Song, Haengseok,Lim, Hyunjung Jade Society for Endocrinology 2014 The Journal of endocrinology Vol.221 No.1

<P>Autophagy is a major cellular catabolic pathway tightly associated with cell survival. The involvement of autophagy in the prolonged survival of blastocysts in the uterus is well established, and it was assumed that ovarian steroid hormones – progesterone (P<SUB>4</SUB>) and estrogens – have important roles in the regulation of autophagy. However, information is scarce regarding whether these hormones regulate autophagy in certain hormone-responsive cellular systems. In this study, we investigated the effects of estrogen and P<SUB>4</SUB> on autophagic response in the uteri of pregnant mice and in ovariectomized (OVX) mice treated with hormones. During pregnancy, autophagic response is high on days 1 and 2 when the uterus shows an inflammatory response to mating, but it subsides around the time of implantation. Dexamethasone treatment to day 1 pregnant mice reduced autophagy in the uterus. In OVX mouse uteri, estrogen or P<SUB>4</SUB> reduces autophagic response within 6 h. Glycogen content in OVX uteri was increased by 3-methyladenine treatment, suggesting that autophagy is involved in glycogen breakdown in the hormone-deprived uterus. The classical nuclear receptor antagonists, ICI 182 780 or mifepristone, lead to the recovery of the autophagic response in OVX uteri. The suppression of autophagy by 17β-estradiol is inversely correlated with the accumulation of phospho-mouse target of rapamycin, and rapamycin treatment is moderately effective in the upregulation of autophagic response in OVX mouse uteri. Collectively, this study establishes that the uterine autophagy is induced in hormone-derived environment and is suppressed by hormone treatment. Uterine autophagy may have multiple functions as a responsive mechanism to acute inflammation and as an energy provider by breaking down glycogen under hormone deprivation.</P>

Myeloid SIRT1 regulates macrophage infiltration and insulin sensitivity in mice fed a high-fat diet

Ka, Sun-O,Song, Mi-Young,Bae, Eun Ju,Park, Byung-Hyun Society for Endocrinology 2015 The Journal of endocrinology Vol.224 No.2

<P>Inflammation is an important factor in the development of insulin resistance. SIRT1, a class 3 histone/protein deacetylase, has anti-inflammatory functions. Myeloid-specific deletion of <I>Sirt1</I> promotes macrophage infiltration into insulin-sensitive organs and aggravates tissue inflammation. In this study, we investigated how SIRT1 in macrophages alters tissue inflammation in the pancreas as well as liver and adipose tissue, and further explored the role of SIRT1 in locomotion of macrophages. Myeloid-specific <I>Sirt1</I>-deleted mice (mS1KO) and WT littermates were fed a 60% calorie high-fat diet (HFD) for 16 weeks. Tissue inflammation and metabolic phenotypes were compared. Bone marrow macrophages (BMMs) from WT or mS1KO mice were used in <I>in vitro</I> chemotaxis assays and macrophage polarization studies. mS1KO mice fed a HFD exhibited glucose intolerance, reduced insulin secretion, and insulin sensitivity with a slight decrease in body weight. Consistent with these results, pancreatic islets of mS1KO mice fed a HFD displayed decreased mass with profound apoptotic cell damage and increased macrophage infiltration and inflammation. Liver and adipose tissues from mS1KO HFD mice also showed greater accumulation of macrophages and tissue inflammation. Results from <I>in vitro</I> experiments indicated that deletion of myeloid <I>Sirt1</I> stimulated proinflammatory M1-like polarization of BMMs and augmented the adipocyte-mediated macrophage chemotaxis. The latter effect was accompanied by increased expression and acetylation of focal adhesion kinase, as well as nuclear factor kappa B. Our results indicate that myeloid SIRT1 plays a crucial role in macrophage polarization and chemotaxis, and thus regulates the development of HFD-induced pancreatic inflammation and insulin secretion, and metabolic derangements in liver and adipose tissue.</P>

Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells

Choi, H. K.,Yang, J. W.,Roh, S. H.,Han, C. Y.,Kang, K. W. SOCIETY FOR ENDOCRINOLOGY PUBLICATION 2007 Endocrine-related cancer Vol.14 No.2

Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells

Chung, Hyunju,Li, Endan,Kim, Yumi,Kim, Sehee,Park, Seungjoon Society for Endocrinology 2013 The Journal of endocrinology Vol.218 No.1

<P>Ghrelin, an endogenous ligand for the GH secretagogue receptor (GHS-R) receptor 1a (GHS-R1a), has been implicated in several physiologic processes involving the hippocampus. The aim of this study was to investigate the molecular mechanisms of ghrelin-stimulated neurogenesis using cultured adult rat hippocampal neural stem cells (NSCs). The expression of GHS-R1a was detected in hippocampal NSCs, as assessed by western blot analysis and immunocytochemistry. Ghrelin treatment increased the proliferation of cultured hippocampal NSCs assessed by BrdU incorporation. The exposure of cells to the receptor-specific antagonist <SMALL>d</SMALL>-Lys-3-GHRP-6 abolished the proliferative effect of ghrelin. By contrast, ghrelin showed no significant effect on cell differentiation. The expression of GHS-R1a was significantly increased by ghrelin treatment. The analysis of signaling pathways showed that ghrelin caused rapid activation of ERK1/2 and Akt, which were blocked by the GHS-R1a antagonist. In addition, ghrelin stimulated the phosphorylation of Akt downstream effectors, such as glycogen synthase kinase (GSK)-3β, mammalian target of rapamycin (mTOR), and p70<SUP>S6K</SUP>. The activation of STAT3 was also caused by ghrelin treatment. Furthermore, pretreatment of cells with specific inhibitors of MEK/ERK1/2, phosphatidylinositol-3-kinase (PI3K)/Akt, mTOR, and Jak2/STAT3 attenuated ghrelin-induced cell proliferation. Taken together, our results support a role for ghrelin in adult hippocampal neurogenesis and suggest the involvement of the ERK1/2, PI3K/Akt, and STAT3 signaling pathways in the mediation of the actions of ghrelin on neurogenesis. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and activation of mTOR/p70<SUP>S6K</SUP> contribute to the proliferative effect of ghrelin.</P>

IGFBP5 mediates high glucose-induced cardiac fibroblast activation

Song, Seung Eun,Kim, Yong-Woon,Kim, Jong-Yeon,Lee, Dong Hyup,Kim, Jae-Ryong,Park, So-Young Society for Endocrinology 2013 Journal of molecular endocrinology Vol.50 No.3

<P>This study examined whether IGF-binding protein 5 (IGFBP5) is involved in the high glucose-induced deteriorating effects in cardiac cells. Cardiac fibroblasts and cardiomyocytes were isolated from the hearts of 1- to 3-day-old Sprague Dawley rats. Treatment of fibroblasts with 25 mM glucose increased the number of cells and the mRNA levels of collagen III, matrix metalloproteinase 2 (<I>MMP</I><I>2</I>), and <I>MMP9</I>. High glucose increased ERK1/2 activity, and the ERK1/2 inhibitor PD98059 suppressed high glucose-mediated fibroblast proliferation and increased collagen III mRNA levels. Whereas high glucose increased both mRNA and protein levels of IGFBP5 in fibroblasts, high glucose did not affect IGFBP5 protein levels in cardiomyocytes. The high glucose-induced increase in IGFBP5 protein levels was inhibited by PD98059 in fibroblasts. While recombinant IGFBP5 increased ERK phosphorylation, cell proliferation, and the mRNA levels of collagen III, <I>MMP2</I>, and <I>MMP9</I> in fibroblasts, IGFBP5 increased c-Jun N-terminal kinase phosphorylation and induced apoptosis in cardiomyocytes. The knockdown of IGFBP5 inhibited high glucose-induced cell proliferation and collagen III mRNA levels in fibroblasts. Although high glucose increased IGF1 levels, IGF1 did not increase IGFBP5 levels in fibroblasts. The hearts of Otsuka Long-Evans Tokushima Fatty rats and the cardiac fibroblasts of streptozotocin-induced diabetic rats showed increased IGFBP5 expression. These results suggest that IGFBP5 mediates high glucose-induced profibrotic effects in cardiac fibroblasts.</P>

Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma

Park, Seog Yun,Jung, Yuh-S,Ryu, Chang Hwan,Lee, Chang Yoon,Lee, You Jin,Lee, Eun Kyung,Kim, Seok-Ki,Kim, Tae Sung,Kim, Tae Hyun,Jang, Jeyun,Park, Daeyoon,Dong, Seung Myung,Kang, Jae-Goo,Lee, Jin Soo,R Society for Endocrinology 2015 Endocrine-related cancer Vol.22 No.4

<P>We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11–8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68–15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03–8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients.</P>

Cysteamine prevents vascular leakage through inhibiting transglutaminase in diabetic retina

Lee, Yeon-Ju,Jung, Se-Hui,Hwang, JongYun,Jeon, Sohee,Han, Eun-Taek,Park, Won Sun,Hong, Seok-Ho,Kim, Young-Myeong,Ha, Kwon-Soo Society for Endocrinology 2017 The Journal of endocrinology Vol.235 No.1

<P>Cysteamine (an aminothiol), which is derived from coenzyme A degradation and metabolized into taurine, has beneficial effects against cystinosis and neurodegenerative diseases; however, its role in diabetic complications is unknown. Thus, we sought to determine the preventive effect of cysteamine against hyperglycemia-induced vascular leakage in the retinas of diabetic mice. Cysteamine and ethanolamine, the sulfhydryl group-free cysteamine analogue, inhibited vascular endothelial growth factor (VEGF)-induced stress fiber formation and vascular endothelial (VE)-cadherin disruption in endothelial cells, which play a critical role in modulating endothelial permeability. Intravitreal injection of the amine compounds prevented hyperglycemia-induced vascular leakage in the retinas of streptozotocin-induced diabetic mice. We then investigated the potential roles of reactive oxygen species (ROS) and transglutaminase (TGase) in the cysteamine prevention of VEGF-induced vascular leakage. Cysteamine, but not ethanolamine, inhibited VEGF-induced ROS generation in endothelial cells and diabetic retinas. In contrast, VEGF-induced TGase activation was prevented by both cysteamine and ethanolamine. Our findings suggest that cysteamine protects against vascular leakage through inhibiting VEGF-induced TGase activation rather than ROS generation in diabetic retinas.</P>